The World Player of the Year limped off at halftime in Tuesday's 2-2 first-leg draw in Paris, having scored the opening goal, and local media reported he would be out of action for some three weeks.
Messi joined Real Madrid's Cristiano Ronaldo and Galatasaray's Burak Yilmaz as the competition's leading scorers with eight goals, but the closest any of his team mates come to that is left back Jordi Alba's two goals.
"Good draw, but very expensive!" was the front-page headline of Barcelona-based daily Sport on Wednesday, after the side notched up valuable away goals but lost Javier Mascherano and possibly Messi to injuries.
Spain's David Villa and Pedro, Chile's Alexis Sanchez, and midfielder-cum-forward Cesc Fabregas, have managed only three goals between them in Europe, trailing way behind the Champions League's leading scorer for the last four seasons in a row.
Barca may need to prove they can survive without the rarely-injured and prolific 25-year-old in the short term.
Sanchez is clearly lacking in confidence, as was seen with two poorly-taken chances on Tuesday, though he did win the penalty for Xavi to put Barca 2-1 up near the end.
Villa has failed to recover his consistency and sharpness since breaking his leg at the Club World Cup in December 2011, and Fabregas has been short of form in recent weeks.
Pedro, who was suspended on Tuesday, should have recovered from a calf injury for the second leg, but has yet to get off the mark in the Champions League this season.
Cristian Tello is another option. The little-used, young winger scored one and set up the second for Messi in their 2-2 draw at Real Zaragoza in La Liga last Saturday, and brings a directness and pace to an attack that at times lacks a cutting edge.
He has scored one goal in the Champions League this season.
Barca coach Tito Vilanova also has headaches in defence after Argentina defender Javier Mascherano was taken off on a stretcher with a torn knee ligament, and the club said he was looking at six weeks on the sidelines.
"Messi and Mascherano are two very important pieces of the team," Xavi told reporters.
"We are having a lot of bad luck in defence, with Carles Puyol and Adriano Correia already out, and now this."
Vilanova lacks specialist centre-backs, a problem that has been evident since Barca failed in their attempts to purchase one at the end of last season. Mascherano himself is a converted midfielder.
Puyol, 34, is recovering from knee surgery and will be hard-pushed to be ready for next week, the versatile Adriano is out with a hamstring tear, and little-used youth-team product Marc Bartra, 22, lacks experience.
The versatile Eric Abidal has just returned to the side a year after having a liver transplant and has yet to play a competitive match.
Another option is to convert holding midfielders Sergio Busquets or Alex Song into centre-backs, which has been tried occasionally, but the last eight of the Champions League is hardly the best time for experimentation.
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- Javier Mascherano
- Champions League